title: Increasing both CoCrMo-alloy particle size and surface irregularity induces increased macrophage inflammasome activation in vitro potentially through lysosomal destabilization mechanisms.
abstract: Recent investigations indicate that innate immune "danger-signaling" pathways mediate metal implant debris induced-inflammatory responses, for example, NALP3 inflammasome. How the physical characteristics of particles (size, shape, and chemical composition) affect this inflammatory reactivity remains controversial. We examined the role of Cobalt-Chromium-Molybdenum (CoCrMo) alloy particle shape and size on human macrophage phagocytosis, lysosomal destabilization, and inflammasome activation. Round/smooth versus irregularly shaped/rough CoCrMo-alloy particles of ∼1 and 6-7 µm diameter were investigated for differential lysosomal damage and inflammasome activation in human monocytes/macrophages. While spherical/smooth 1 µm CoCrMo-alloy particles did not measurably affect macrophage IL-1β production, irregular 1 µm CoCrMo-alloy particles induced significant IL-1β increases over controls. Both round/smooth particles and irregular CoCrMo-alloy particles that were 6-7 µm in size induced >10-fold increases in IL-1β production compared to similarly shaped smaller particles (p < 0.05). Larger irregular particles induced a greater degree of intracellular lysosomal damage and a >3-fold increase in IL-1β versus similarly sized round/smooth particles (at an equal dose, particles/cell). CoCrMo-alloy particle-size-induced IL-1β production was dependent on the lysosomal protease Cathepsin B, further supporting lysosomal destabilization as causative in inflammation. Phagocytosable larger/irregular shaped particles (6 µm) demonstrated the greatest lysosomal destabilization (observed immunofluorescently) and inflammatory reactivity when compared on an equal dose basis (particles/cell) to smaller/spherical 1 µm particles in vitro.
authors.affiliation: Department of Orthopedic Surgery, Rush University Medical Center, 1735 W Harrison MC107, Chicago, Illinois, 60612, USA.
authors.forename: Marco S
authors.initials: MS
authors.lastname: Caicedo
authors.forename: Lauryn
authors.initials: L
authors.lastname: Samelko
authors.forename: Kyron
authors.initials: K
authors.lastname: McAllister
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Jacobs
authors.forename: Nadim J
authors.initials: NJ
authors.lastname: Hallab
mesh_terms: D000497:Alloys / Q000737:chemistry / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D002478:Cells, Cultured; D002857:Chromium / Q000737:chemistry / Q000494:pharmacology; D003035:Cobalt / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008247:Lysosomes / Q000276:immunology* / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008982:Molybdenum / Q000737:chemistry / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010316:Particle Size; D010587:Phagocytosis / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D013499:Surface Properties
chemical_list: D000497:Alloys; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D034741:RNA, Small Interfering; D002857:Chromium; D003035:Cobalt; D008982:Molybdenum; C533912:CTSB protein, human; D002401:Cathepsin B; D020170:Caspase 1
keywords: Cathepsin B; inflammasome; lysosomal destabilization; metal particles; monocytes/macrophages